The strong activation of the clotting cascade that occurs during total hip arthroplasty places patients at increased risk for venous thromboembolism. The risk is higher in those patients with the following predisposing factors, listed in approximate order of importance: hip fracture; malignancy, particularly if associated with chemotherapy; antiphospholipid syndrome; immobility; history of venous thromboemholism; administration of tamoxifen; raloxifene; oral contraceptives or estrogen; morbid obesity; stroke; atherosclerosis; and an American Society of Anesthesiologists physical status classification of 3 or greater. The following risk factors are weak or controversial: advanced age; diabetes mellitus; congestive heart disease; atrial fibrillation; varicose veins; and smoking. However, 50% of patients who develop thromboembolism after total hip arthroplasty have no clinical predisposing factors. In a matched, controlled study, we defined the major genetic predispositions that increase the risk of venous thromboembolism after total hip arthroplasty: deficiency of antithrombin III (< 75%) and protein C (< 70%), and prothrombin gene mutation. Preoperative genetic screening in conjunction with the recognized clinical risk factors can help categorize postoperative venous thromboembolism risk and differentiate patients who can be protected with milder and safer prophylaxis (eg, aspirin, intermittent pneumatic compression) compared with those at higher risk who need to be anticoagulated.